Introduction
This integrative review builds a foundation of knowledge from the scientific literature on cancer-related cachexia and sarcopenia among survivors of hematologic malignancies. Research on cancer-related cachexia and sarcopenia is primarily in solid tumors, frequently pancreatic and gastric cancers, with limited research focused on hematologic malignancies [ 1 ]. A knowledge gap exists in our understanding of cancer-related cachexia and sarcopenia in hematologic carcinomas.
Cancer-related cachexia occurs among up to 80 % of individuals with advanced cancer [ 2 , 3 ]. It is a wasting syndrome, with affected individuals experiencing weight loss of skeletal muscle and fat. The consensus definition of cachexia reached by the international Delphi Group [ 4 ] is “a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism.” Deaths associated with cachexia in oncology are around 20 %, primarily in gastrointestinal malignancies [ 5 ].
According to the international consensus, cancer-related cachexia is staged as pre-cachexia, cachexia, and refractory cachexia [ 4 ]. Several factors impact the progression from pre-cachexia to the refractory cachexia stage, including the type and stage of cancer. Other reasons include inflammation, excess catabolism, and increased metabolism [ 6 ]. The cancers with the highest incidence of cancer-related cachexia in the United States are lung, digestive tract, and Kaposi sarcoma [ 7 ]. The prevalence of cachexia among hematologic malignancies is greater than 40 %, with an average weight loss of 7 % [ 8 , 9 ].
A similar yet distinct wasting process, also part of the definition of cachexia, is cancer-related sarcopenia. It differs by the focus on skeletal muscle loss and its subsequent impact on function. A precise definition for sarcopenia lacks universal acceptance [ 10 ]. Sarcopenia related to cancer is secondary sarcopenia, while sarcopenia related to natural aging is primary sarcopenia [ 11 ]. The number of cancer patients who suffer from sarcopenia ranges from 37.6 % in breast cancer [ 12 ] to 60 % in gastric cancers [ 13 ]. Although common, little research identifies and supports patients with hematologic malignancies who are cachectic and sarcopenic.
Many studies use the terms cachexia and sarcopenia interchangeably, limiting progress in research. From this review, the predominant themes in research are radiologic measurement techniques on cancer-related cachexia and sarcopenia; prognostication of overall survival (OS) and progression-free survival (PFS); the effects of transplant and chimeric antigen receptor T-cell therapy on cancer-related cachexia and sarcopenia; and sex-based differences in the effects of cancer-related cachexia and sarcopenia.
Objective
The objective of this integrative review is to provide a synthesis of studies in peer-reviewed journals on cancer-related cachexia and sarcopenia among patients with hematologic malignancies to improve awareness and understanding for healthcare providers.
Methods
Eligibility criteria
The PICOS statement that guided the eligibility criteria for this review was as follows:
P articipant – patients with malignant hematology diagnoses;
I ndicator – cancer cachexia or sarcopenia;
C omparison – non-cachexic/nonsarcopenic patient;
O utcome – incidence, prevalence, quality of life, and survival (OS, PFS, event-free), tolerance to treatment, and adverse events; and
S tudy design – interventional studies of any type [ 14 ].
This integrated review includes studies published in English between 2012 and 2022 of adult patients with hematologic malignancies that contain data related to cancer-related cachexia or sarcopenia. Studies with a pediatric population or animals as the study subjects were excluded, as were abstracts, conference proceedings, and dissertations.
Search strategy
This integrated review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [ 15 ]. Studies from Ovid MEDLINE, CINAHL Complete, Embase, and Web of Science databases are included. The authors used medical subject-heading terms and keywords related to hematologic malignancy and cancer-related cachexia or sarcopenia listed in Table 1 .
Study selection
The screening included evaluating titles and abstracts, followed by full-text assessments for eligibility by two authors (SMT and TMM).
Authors used Covidence software to retrieve articles by applying the selection criteria. For articles with disagreements, the investigators discussed until resolution.
Study synthesis
Following the data extraction into a table format, both authors grouped the studies according to their outcomes. The major outcomes were grouped and tabulated, and major findings were coded for population, study design, and outcomes. This coding provided the foundation for the comparison of studies and results of findings. Most studies were retrospective and qualitative and not amenable to meta-analysis. The studies are grouped alphabetically in Table 2 for cachexia and Table 3 for sarcopenia.
Results
Study characteristics
Covidence software extracted 1,097 publications and removed 216 duplicates. The authors screened 881 publications against the title and abstract, with 691 excluded, resulting in 190 remaining for full-text review for eligibility. Authors SMT and TMM excluded one hundred sixty-four publications. This resulted in twenty-six publications focused on cancer-related cachexia or sarcopenia in malignant hematology. Three more studies were included from reference lists for twenty-nine studies for this review ( Fig. 1 .)
Tables 2 and 3 summarize extracted data and include (1) study identification (authors, year of publication, setting/country, study design, and study duration); (2) baseline characteristics (diagnoses and sample); (3) results; and (4) methodological quality assessment. The methodological quality assessment of the studies was evaluated using the Critical Appraisal Skills Programme [ 16 ]. These tools assess various study designs for trustworthiness, results, and relevance. InfoCASP UK advised (personal communication, October 7, 2022) using the case-control tool for retrospective studies.
Thirteen studies examined cachexia in Table 2 , and 16 studies focused on sarcopenia in Table 3 per title; however, because of the interchangeability of the terms, three studies examining cachexia include the terms sarcopenia and adipopenia in their results [ 17 – 19 ]. The majority of studies were conducted in Asia, including Turkey (n = 12, 41.49 %), followed by the United States (n = 9, 31.0 %) and Europe (n = 8, 27.6 %). Twenty-three studies (79.3 %) had a retrospective study design, including one that was both retrospective and prospective. No randomized controlled studies were found.
Participant characteristics
Not all studies reported sample size or specific diagnoses. This review represents data from 5419 participants. Most participants were diagnosed with non-Hodgkin’s lymphoma (NHL) (n = 3424). Most cases (n = 2913) were diffuse large B-cell lymphoma (DLBCL). Eight hundred ninety-four participants had leukemia, with the majority having acute myelogenous leukemia.
Health Outcomes
Survival
Similar to solid-tumor patients, OS and PFS were reduced among patients with hematologic malignancies with [ 17 , 20 – 24 ] cachexia and sarcopenia. In a retrospective study evaluating clinical outcomes for patients with DLBCL, males with sarcopenia had PFS reduced to 5.4 months, compared to nonsarcopenic patients who had PFS of 72.3 months ( P < .005) [ 17 ]. Overall survival was also impacted for these cachectic male patients who had an OS of 30.2 months, while OS among noncachectic males was not reached ( P = .02). Furthermore, male patients with fat loss, or adipopenia, experienced an even shorter OS of 21.6 months vs males without adipopenia, for whom OS was not reached ( P = .04). In a similar retrospective study on DLBCL [ 18 ], PFS was significantly longer among nonadipopenic patients, with a median PFS of 49.4 months, and among adipopenic patients, a median PFS of 13.6 months ( P = .001). OS was significantly different among nonadipopenic patients (57.1 months) compared to adipopenic patients (25.7 months, P = .034). OS and PFS were not significantly different between males and females. A similar retrospective study included mantle cell lymphoma and DLBCL [ 25 ]. Cachectic patients experienced significantly worse PFS ( P = .044) and OS ( P = .004). In a large cross-sectional study [ 20 ] of 1030 cancer patients 70 years of age and older in France, 55 patients had hematologic malignancies, and the 6-month OS rate for cachexia patients was 66.1 % compared to 84.5 % in non-cachexic patients (log--rank, P < .001). After adjustments were made for age, inpatient status, anticancer treatment, number of prescribed medications, cognitive impairment, cancer status, and metastatic status, the 6-month mortality risk was higher for cachexic patients, indicating the prognostic impact of cachexia in relation to other variables. Additional studies in aggressive lymphoma have been performed with the inclusion of chemo-immunotherapy toleration and response in patients with cancer-related cachexia and sarcopenia.
In a study of 187 patients being treated for DLBCL with rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP) to determine whether sarcopenia affected their clinical outcomes, the 5-year PFS was 35.3 % among patients with sarcopenia compared to the 65.8 % in nonsarcopenic patients ( P < .001) [ 26 ]. In a comparable study performed in a different country of 120 DLBCL patients receiving R-CHOP, OS was significantly better in the non-sarcopenic group ( P = .004) [ 27 ]. Progression-free survival between the sarcopenic and nonsarcopenic groups was trending toward statistical significance ( P = .053). In a study [ 21 ] focused on 80 elderly patients with DLBCL, PFS was significantly better for the nonsarcopenic group (median PFS, 32.8 months) compared to the sarcopenic group (median PFS, 13 months) ( P = .001). In addition, the 2-year OS in the sarcopenic group was 46 % compared to 84 % in the nonsarcopenic group ( P = .002). These patients were also treated with chemo-immunotherapy [ 21 ], with varying combinations that differed from R-CHOP.
In contrast to prior reported studies, one study [ 28 ] of 207 patients with DLBCL examined the prevalence and prognostic value of sarcopenia among older patients treated with chemotherapy with rituximab. Sarcopenia was not predictive of OS or PFS ( P = .260). However, in subgroup analysis, significant findings were shown between the sexes, which will be discussed later in the sex-based differences section [ 28 ].
Lucijanic and colleagues investigated the association of OS and PFS with sarcopenia. [ 23 , 24 ]. Data was retrospective and from a single institution. The psoas muscle area (PMA) was studied from CT scans of 104 patients with DLBCL, who were treated with dose-adjusted etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), and rituximab. Patients who lost 21 % or more PMA had significantly worse OS and PFS ( P < .001). In Hodgkin lymphoma (HL) [ 23 ], sarcopenia measurements of the psoas muscle index (PMI) instead of the PMA were studied for their prognostic properties. The median PMI of 49 patients was 572.5 mm 2 /m 2 . PMI less than 582 mm 2 /m 2 had significantly worse PFS ( P = .009) compared to higher PMI. However, PMI was not prognostic for OS.
Decreased OS and improved prognostication were evaluated among patients with HL by Koyuncu and colleagues [ 22 ]. OS was significantly lower ( P = .001) among patients with HL who had low muscle mass, measured by CT/PET at the time of diagnosis and following two cycles of chemotherapy. These investigators found that by integrating muscle mass data into the traditional International Prognostic Score for HL, prognostication could be improved.
Treatment responses
Cancer-related cachexia and sarcopenia decrease the ability to tolerate treatment and thus diminish the depth and length of response. In a study [ 19 ] that developed a prognostic nutritional index (PNI) for DLBCL patients, those with a lower PNI had higher treatment-related mortality compared to those with a high prognostic nutritional index (15.9 % vs 5.7 %). Similarly, treatment discontinuation was more significant (43.5 %) with a low PNI than 8.8 % with a high PNI. As expected, the complete response (CR) rates were lower in the low-PNI group (60.3 %) than in the high-PNI group (87.6 %) ( P < .001). In another retrospective study by the same authors [ 29 ], from 267 patients with DLBCL, a cachexia index (CXI) was calculated using the L3 skeletal muscle index and pectoralis muscle. These patients were treated with R-CHOP. Three groups were formed: low CXI, intermediate CXI, and high CXI. Rates of CR were significantly lower in the low-CXI group ( P < .001). When 25 % or greater dose adjustments were required, patients in the lower CXI groups had significantly lower CR rates of 50 %, compared to 66.7 % in the intermediate CXI and 93.8 % in the high CXI groups ( P = .031). Interestingly, there were no differences in rates of CR between the groups who discontinued treatment early. These patients uniformly had low CR rates. Likewise, in a study focused on patients with DLBCL treated with R-CHOP who had sarcopenia, the rate of CR was lower in the sarcopenic group (58.7 %) compared to the nonsarcopenic group (80.9 %, P = .004) [ 26 ]. However, when responses to treatment were evaluated for those patients who stopped treatment for causes other than disease progression, there was no significant difference in CR rate between the sarcopenic and nonsarcopenic patients (78.1 vs 90.2 %, P = .076). Thus, the inability to tolerate planned treatment was the reason for the difference in CR rates. Consistent findings in a similar study [ 30 ] DLBCL patients receiving CHOP-R showed significantly lower CR rates and progressive disease ( P = .003).
In evaluating muscle density, one study [ 31 ] of patients with DLBCL focused on low muscle mass and low muscle density (LMD). Interestingly, patients with LMD experienced premature termination of chemotherapy (28.9 % vs. 12.1 %, P = .02). The primary reason for early discontinuation of treatment was treatment-related toxicity (27.3 % for patients with LMD vs 20 % for patients without LMD), also associated with death (36.4 % for patients with LMD vs 13.3 % without LMD). This is the only study focused on muscle density and muscle mass, further dividing sarcopenia based on density and mass of muscle and then relating it to early termination of chemotherapy treatment and death.
Hematologic parameters
Nutritional deficiencies can cause pancytopenia [ 32 ]. Megaloblastic anemia is associated with vitamin B12 and folate deficiencies. Copper deficiency can mimic myelodysplastic syndromes; vitamin C deficiency is associated with pancytopenia. Consequently, it is not surprising that in one retrospective study [ 19 ], patients with DLBCL treated with first-line R-CHOP who were in the low PNI group experienced toxicity grade 3 or greater for neutropenia of 91.3 % vs. 78.0 % in high PNI; thrombocytopenia of 43.5 % vs. 18.9 % in high PNI; and febrile neutropenia of 53.6 % vs. 22.0 % in high PNI. This difference was associated with treatment discontinuation in 43.5 % in low PNI compared to 8.8 % in high PNI.
A recent retrospective study [ 29 ] was conducted on patients with DLBCL who were being treated with R-CHOP. A CXI was calculated with three groups formed and labeled as high CXI, intermediate CXI, and low CXI. The CXI is calculated by multiplying skeletal muscle index (cm2/m2) with serum albumin (g/dL) and dividing the result by absolute neutrophil and lymphocyte counts. Grades 3 to 4 anemia, thrombocytopenia, and febrile neutropenia occurred significantly less frequently in the high-CXI group (15.6 %, 21.4 %, and 23.7 %) than in the intermediate CXI (30.6 %, 36.1 %, and 44.4 %), and low CXI (26.3 %, 43.9 %, and 36.8 %). Respective P values of .038, P < .001, and P = .022 were reported.
Identification of patients
Markers
Several studies in this review focused on ways to improve the identification of patients at increased risk for poor outcomes from cachexia and sarcopenia. In a retrospective study of 80 patients with DLBCL, a cachexia score was developed that included fat-tissue loss and sarcopenia assessed by CT scans among elderly patients being treated with chemo-immunotherapy [ 18 ]. Most of the patients were female and had a median baseline BMI of 23.91. Adipopenic patients had higher serum lactate dehydrogenase and a higher rate of germinal B-cell phenotype. A definition for sarcopenia was established based on CT evaluation. Males with skeletal muscle index (SMI) below 55.8cm2/m2 and females with SMI below 38.9cm2/m2 were considered to have sarcopenia. Differences in OS and PFS were observed between adipopenic and non-adipopenic groups and 2-year OS. Suggestions were made to include a cachexia scoring tool for elderly patients with DLBCL to predict outcomes independently of BMI.
A cross-sectional observational study by Fukushima et al. (2019) classified patients into three groups: non-cachexia, pre-cachexia, and cachexia, using the Glasgow Prognostic Index [ 33 ]. This study included a variety of hematologic malignancies such as lymphoma, acute myelogenous leukemia, acute lymphoblastic leukemia, multiple myeloma, and chronic myelogenous leukemia. Seventy-one healthy controls matched for age and sex were also included. They found that patients with a hematologic malignancy had lower skeletal muscle mass in the lower body and lower limbs. Compared to healthy controls, they also demonstrated lower levels of SMI, handgrip strength, and isometric knee-extensor strength. The authors concluded that decreased muscle function in hematology patients was due to reduced physical activity, malnutrition, and cancer-related cachexia from the disease and treatment rather than other factors. This study highlights the importance of providing additional support to patients and their caregivers during treatment through nutrition counseling and physical therapy to improve treatment tolerability and maintain muscle function.
Go and colleagues [ 19 ] developed a PNI to evaluate its association with clinical outcomes and survival rates. The goal was to identify a valid cachexia marker that could predict the prognosis of patients with DLBCL treated with R-CHOP. Positive correlations were discovered between the PNI and the pectoralis muscle SMI. Furthermore, serum albumin was strongly associated with PNI (R2 = 0.69, P < .001). As expected, the low-PNI group had lower pectoralis muscle and L3 SMI. In multivariate analyses, low PNI, sarcopenia, and higher international prognostic index scores were independent prognostic factors for poor PFS and OS. Prognostic capabilities improved by adding the PNI to traditional staging for DLBCL.
A recent study by Go and colleagues [ 29 ] focused on the CXI, calculated from the L3 SMI, and the pectoralis muscle from patients with DLBCL treated with R-CHOP. The study compared three groups: the high CXI group, the intermediate CXI group, and the low CXI group. The study results revealed that the low-CXI group had a poorer performance status than the higher-CXI groups. Moreover, the low CXI group also had more B symptoms, a higher proportion of Ann Arbor stages III to IV disease, and a higher National Comprehensive Cancer Network International Prognostic Index than the higher CXI groups. Multivariate analysis showed that underweight BMI, higher National Comprehensive Cancer Network International Prognostic Index, and low CXI were independent negative prognostic indicators for PFS. Improving our understanding of the pathophysiology of cancer-related cachexia is necessary to enhance support during treatment.
A study by Karmali et al. [ 25 ] evaluated the potential prognostic usefulness of CXI in patients with aggressive NHL. Seventy-six individuals were diagnosed with DLBCL, and ten were diagnosed with mantle cell lymphoma. According to the study, half of the patients suffered from muscle loss. Patients with low skeletal muscle mass index (SMI) had similar outcomes to those with high SMI ( P = .74). In this study, the presence of cachexia assessed by CXI did not impact PFS after adjusting for LDH and stage but was associated with worse OS ( P = .032).
A retrospective study of 1347 DLBCL patients from China identified cachexia-inducing factors (CIFs) based on two molecular subtypes: Cluster A and Cluster B [ 34 ]. Seven CIFs were identified as associated with OS. This has limited utility currently. However, it has the potential for use in the future if the molecular subtypes are incorporated as standard practice in diagnosing and staging DLBCL.
In 2013, researchers conducted a cross-sectional study [ 35 ] to determine if there were any differences in C-reactive protein (CRP), hemoglobin, and albumin among patients with hematologic malignancies (10 patients with HL and 45 patients with NHL) compared to nonhematologic patients with cachexia. Significant differences were found in mean CRP levels between hematologic and nonhematologic patients (15.98 vs. 28.71, P = .48). When the CRP levels were analyzed by cachexia status, patients with cachexia had a mean CRP of 34.18. In contrast, patients without cachexia had a mean CRP of 17.57 ( P = .021). There were no significant differences between hematologic and non-hematologic cachexia patients, suggesting common features of cachexia. Cachectic patients had lower levels of hemoglobin compared to noncachectic patients ( P = .039) but not between hematologic and nonhematologic ( P = .33). Albumin levels were significantly lower in both cachectic (34.95) and noncachectic patients (39.85) ( P = .001), as a group and between hematologic and nonhematologic patients ( P = .004). In a prospective observational study by Mallard et al. [ 27 ], routine laboratory markers were examined to identify predictive markers of cachexia in NHL (n = 84), HL (n = 30), and multiple myeloma (n = 31). This study identified CRP as a key predictive marker. At diagnosis, a CRP level greater than 54 mg/L was found to be a risk factor for developing cachexia during treatment ( P = .023). Furthermore, the traditional prognostic scores were found to have no significant correlation with cachexia. A cross-sectional study conducted in France [ 20 ] assessed the prevalence of cachexia in 1030 patients, with 55 of them diagnosed with hematologic malignancy before treatment. This review included patients with myelodysplastic syndromes and acute leukemia, which was rare in other studies reviewed. The prevalence of cancer-related cachexia was 51.8 %. The prevalence of hematologic patients was similar at 50.9 %. Elevated CRP levels were significantly lower than the CRP risk factor identified in a previous study, which was associated with cachexia ( P = .020). Nutritional support strongly correlated with cachexia (Cramer’s V = 0.38, P < .001).
In a retrospective study of 414 patients with primary myelofibrosis (PMF), a new CXI was developed, including serum albumin and cholesterol levels [ 36 ]. Prognostic ability significantly shortened survival when cholesterol and albumin levels fell below the normal range in all patients ( P < .01). A cutoff value of 122 mg/dL for total cholesterol and 4.3 g/dL for serum albumin predicted survival. The authors created an operational CXI for PMF using serum albumin and cholesterol levels. The PMF CXI is either favorable (CXI 0) or unfavorable (CXI 1 and 2). It remained statistically significant even when tested alongside cytogenetic and molecular information in contemporary prognostic models. The PMF CXI has the potential for worldwide use, especially in healthcare facilities without access to cytogenetic or molecular laboratory results.
Go et al. (2020) evaluated the Geriatric Nutritional Risk Index (GNRI) for its clinical impact on clinical outcomes alone and combined with sarcopenia [ 37 ]. Groups were formed based on retrospective data of 228 patients with DLBCL treated with R-CHOP in the GRNI. There were two groups: high cachexia risk (HCR) and low cachexia risk (LCR). The HCR had a GNRI of less than 82, sarcopenia-both, or GNRI of 82 to 95 with sarcopenia −L3/PM alone. Grade 3-related treatment toxicities were significantly more frequent in the HCR group vs the LCR group ( P = .07).
Radiologic evaluation of body composition
Routine CT and PET-CT scans are performed in NHL and HL for staging and treatment response assessment. Many studies in this review utilized radiographic images to evaluate body composition and its correlation with health outcomes. In a retrospective chart review study by Go et al. [ 29 ], CT images were used to evaluate the correlation between body composition indices and R-CHOP treatment-related adverse reactions among 201 DLBCL patients. The most common non-hematologic toxicities observed during treatment were neurotoxicity, vomiting, diarrhea, and other gastrointestinal effects of varying severity (grades III and IV). The goal of this study was to investigate the correlation between sarcopenia and hospitalizations, dose reductions, or early termination of chemotherapy. Skeletal muscle area, skeletal muscle density (SMD), skeletal muscle index SMI (skeletal muscle gauge = SMI × SMD), and lean body mass were calculated and correlated with grades III and IV toxicities. Out of 201 patients, 71 % experienced grade 3 or 4 toxicity. An increase in the risk of 11 % ( P < .01) for grade 3 to 4 toxicity was observed for every 100 arbitrary units of SMG reduction. For every 5 cm 2 /m 2 reduction in SMI, toxicity was increased by 34 % ( P < .01). With a 5 kg lean body mass reduction, toxicity risk increased by 35 % ( P < .01). This research is the first to demonstrate that skeletal muscle mass and density are better predictors of chemotherapy toxicity than body surface area and BMI.
The psoas muscle index (PMI) [ 23 , 30 ] and psoas muscle area (PMA) [ 24 ] were used in three studies to investigate their potential for improving prognostication in HL and DLBCL. In the study on PMI with DLBCL, the sarcopenic group had a significantly higher age (62.5 years) than the nonsarcopenic group (55.2 years) ( P = .003). The group with sarcopenia had a significantly lower survival rate than the group without sarcopenia ( P = .004). In contrast, in the study with PMI and 49 patients with newly diagnosed HL, PMI was not associated with age. There was no significant difference in PMI between patients with early, intermediate, or advanced disease. Also, PMI was not prognostic for OS. However, lower PMI was significantly associated with PFS ( P = .04), possibly due to the smaller sample size or different diseases.
Lucijanic et al. [ 24 ] retrospectively studied psoas muscle mass in 104 DLBCL patients. Patients with ≥21 % muscle PMA loss had significantly worse OS ( P = .001) and PFS ( P = .001). Before and after treatment, PMA measurements were 1238 mm2 and 1099 mm2, respectively, with R-dose-adjusted etoposide phosphate, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride, and prednisone. There was a noticeable decrease in PMA during the treatment with chemoimmunotherapy, which was statistically significant ( P = .016). There was also a poorer response to chemotherapy ( P = .008). These studies show that radiologic evaluation of sarcopenia provides additional prognostic capability beyond traditional staging for DLBCL and HL.
In Bas et al.’s [ 38 ] study, the prevalence of sarcopenia was determined in 59 patients diagnosed with HL. Following treatment, a retrospective study was conducted using stored images to assess sarcopenia. The study found that lumbar muscle mass decreased significantly ( P ≤ .001), along with muscle metabolism ( P = .004), as measured by the PET-CT scans. In logistic regression, BMI, ECOG performance status, and age significantly correlated with changes in muscle mass after treatment ( P ≤ .001). Sarcopenia was recognized as a natural part of the aging process. However, this small retrospective study found that the condition was accelerated in younger HL patients during treatment.
The impact of skeletal muscle on the prognosis of elderly patients (70+ years of age) with DLBCL who received R-CHOP or reduced-dose R-CHOP was retrospectively studied [ 21 ]. Sarcopenia was measured by analyzing stored CT images at the L3-area muscular tissues selected according to the CT Hounsfield unit. This value was adjusted for height to calculate the lumbar L3 SMI (cm2/m2). This group encountered a lack of consensus in defining sarcopenia using CT scans. As a result, they decided to define sarcopenia using sex-specific cutoffs for linear skeletal muscle index within the inner 80 % of the L3 SMI distribution. They used the minimal P-value approach to arrive at their decision. Men with a muscle mass less than 55.8 cm2/m2 and women with a muscle mass less than 38.9 cm2/m2 were used to define sarcopenia. Patients with sarcopenia were not able to complete planned chemotherapy vs nonsarcopenic ( P = .02). Sarcopenia and hypoalbuminemia in multivariate analysis were predictive of OS ( P = .04 and P = .007) and PFS ( P = .01 and P = .02) when BMI, age, and IPI were included.
An additional retrospective study of 164 patients with DLBCL investigated the association of muscle density and muscle mass, measured by CT scans. In addition, this study investigated the association between comorbidities, treatment responses, and treatment toxicity [ 31 ]. Overall, muscle mass in the entire group was lower compared to the healthy population at 40.5 cm 2 /m 2 vs 47.4 cm 2 /m 2 ( P < .001). The percentage of individuals with LMD who terminated chemotherapy prematurely was significantly different from those with normal muscle density (28.9 % vs. 12.1 %, P = .02). The primary reason for early termination of chemotherapy was toxicity (27.3 % of patients with LMD vs. 20 % of patients without LMD). There were also early deaths among 36.4 % of patients with LMD compared to 13.3 % of patients without LMD. From this study, we conclude that—in addition to measuring sarcopenia—measuring muscle mass and density provides prognostic information that refines our understanding of sarcopenia’s impact on health outcomes.
Transplant and chimeric antigen receptor T-cell (CAR-T) therapy
One study looked at the acute effects of autologous hematopoietic stem cell transplantation (HSCT) on cachexia. Measurements were taken 30 days (+/− 10 days) before and after transplant. Specific outcomes included physical function, body composition, quality of life, energy expenditure, and testosterone [ 39 ]. Measurements were taken from 21 individuals, including 15 diagnosed with multiple myeloma and 6 diagnosed with NHL. Significant decreases were reported following transplant in the 6-minute walk test (6MWT; P = .014), lean mass ( P = .002), and fat mass ( P = .02). Nausea and fatigue increased significantly at follow-up ( P = .039). Significant predictors of reduced aerobic activity ( P < .001) were steroid exposure and recent weight change. Interleukin B, interleukin 6, and tumor necrosis factor cytokines were not significantly changed. Several instruments were used to measure patient-reported outcomes. The Functional Assessment of Chronic Illness Therapy – Fatigue score worsened on the social scale from pretransplant to follow-up, including social well-being (−1.0 [−3.5, −0.1]; P = .027) and fatigue (−5.0 [−11.3, −0.2]; P = .039). Vitality score measured by the Health Survey (SF-36) worsened from pretransplant to follow-up at (−2.0 [−4.3, −0.1]; P = .039). This small study did not identify the underlying mechanisms for the decline in physical function with decreased lean and muscle mass and increased symptoms 30 days following transplant.
Two studies focused on autologous HSCT [ 40 , 41 ]. One study was a prospective correlational of 121 patients who underwent HSCT for hematologic malignancies, 91 patients with NHL, 17 with HL, and 13 others. No correlation was found between the HSCT comorbidity index and psoas indices. However, there was a significant positive correlation between Karnofsky ‘s performance status among men ( P = .05). The following section describes differences in outcomes reported between men and women. Patients who had a lower PMI had a higher rate of complications compared to patients with a higher PMI ( P = .001). There was also a strong association between sarcopenia and 100 days (about three and a half months) post-transplant readmission for the whole cohort when controlling for age, sex, BMI, and Karnofsky performance status, with P < .001 for total PMI and lean PMI. In the retrospective study [ 41 ] of 142 patients with multiple myeloma treated with autologous HCT, 72 (51 %) patients had sarcopenia. Baseline characteristics were not significantly different between sarcopenic and nonsarcopenic patients. Sarcopenic patients (12.5 %) experienced more cardiovascular complications than nonsarcopenic patients (2.9 %) ( P = .03). Sarcopenia was not associated with overall mortality. Increasing BMI at transplant was correlated with worse OS ( P = .02). PFS was not correlated with sarcopenia.
Further studies with aggressive treatments included allogeneic stem cell transplants; these studies examined the prognostic significance of sarcopenia. The largest study [ 42 ] Included 859 patients, 465 with acute myelogenous leukemia, 219 with acute lymphoblastic leukemia, 164 with myelodysplastic syndromes, and 11 others. This study described the prevalence of sarcopenia from a retrospective cohort and found that 33.7 % of patients had sarcopenia pretransplant. This was an independent predictor of higher non-relapse mortality of 25.3 % in patients with sarcopenia vs 15.9 % in nonsarcopenic patients ( P = .001). Patients with sarcopenia had a more extended hospitalization of 37.2 days compared to 31.5 days for patients without sarcopenia ( P < .001). Patients with sarcopenia also had inferior OS at two years ( P < .001) and a 1.4-fold risk of all-cause mortality ( P = .003). These robust data on a large data set provide compelling evidence for measuring sarcopenia pretransplant. Similar findings were reported by Lin and colleagues [ 43 ] from retrospective data of 146 older patients diagnosed with NHL (138) and HL (8) 50 years or older. They reported that 80 (55 %) patients were sarcopenic before transplant. Non-relapse mortality was significantly associated with pretransplant sarcopenia ( P = .044). Patients who had combined pretransplant sarcopenia and HSCT comorbidity index of greater than or equal to 3 had the worst 3-year OS of 41 %.
Consistent findings were reported from retrospective data on 172 patients (113 with acute myeloid leukemia, 55 with acute lymphoblastic leukemia, and 4 with acute undifferentiated leukemia) who underwent allogeneic HSCT [ 44 ]. CT measurements at the L3 vertebra assessed muscle mass loss. Three groups were formed from the data based on low, middle, and high muscle mass. The mean length of inpatient hospitalization in days was significantly longer in the low-SMI group, 66.0, compared to 54.5 in the middle muscle mass group and 54.0 in the high muscle mass group ( P = .03). The 2-year non-relapse mortality rate did not differ among the three groups. The two-year OS between the three groups was significantly different (36.4 % vs. 50.5 % vs. 66.3 %, P = .005), with the low SMI having the lowest 2-year OS of 36.4 %. Low SMI was not significant with higher-risk diseases.
One study of sarcopenia and chimeric antigen receptor T-cell (CAR-T) therapy is included in this review, indicating an area for future research [ 45 ]. Through a retrospective cohort study of 70 adult lymphoma patients who received CAR-T therapy, the researchers found that increased CRP (≥3) ( P = .01) and an increased weight-loss grading-scale score (≥2) ( P = .02) at the time of transplant were associated with increased odds of relapse at 90 days. Albumin less than 3.5 ( P = .02) and PNI less than 44 ( P = .05) were significantly associated with lower disease-free survival. However, median disease-free survival could not be calculated at the time of publication. Evaluation of cachexia before CAR-T therapy may help to identify patients who could benefit from intense dietary and physical therapy before CAR-T treatment.
Sex-based differences
Several studies reported differences in outcomes between men and women. In the retrospective group of patients diagnosed with DLBCL, males with sarcopenia had a reduced PFS of 5.4 months vs 72.3 months in the nonsarcopenic group ( P < .001). This was also true for OS, with male patients having an OS of 30.2 months vs not reached for the nonsarcopenic group ( P = .02). In addition, male patients with adipopenia had a decreased OS of 21.6 months vs not reached for the nonadipopenic group ( P = .04). The authors concluded that cachexia in aggressive lymphoma has prognostic utility in males but not females. In contrast, Camus and colleagues [ 18 ] found no statistically significant differences in OS or PFS between males and females with DLBCL and treated with R-CHOP. In a prospective correlational study[ 40 ], only men had a significant correlation between psoas indices and better Karnofsky performance status. Also noted for men was that a decrease of 100 units in the total psoas index was associated with an increased HR for non-relapse mortality (HR, 2.37 P = .041). The total psoas index in women did not have this effect. One explanation for this difference was that the study was underpowered to detect this effect in women. Noted in another retrospective study [ 30 ] involving DLBCL, there was a tendency towards worse PFS ( P = .053) and significantly worse response to treatment in male sarcopenic patients ( P = .033). This study included fifty-four females and 66 males. It is unclear why there are differences between the studies. However, the effects of sarcopenia and cachexia, from retrospective data in DLBCL, are significant in men more than women from this review. For transplanted patients, pretransplant sarcopenia was correlated with post-transplant sarcopenia for females ( P = .046). In another retrospective study of 207 patients with DLBCL, no significant differences were noted between males and females for predictive factors of the R-IPI and B symptoms. Of the 217 patients, 73 males and 42 females met the criteria for sarcopenia ( P = .101). The difference in OS was reported as significant for sarcopenic males ( P = .001) but not females ( P = .444). Also, the rate of disease progression was significantly higher for males (68 % vs 17 %, P = .020) and significantly lower among females (44 % vs 91 %, P = .020), comparing sarcopenic to nonsarcopenic[ 28 ].To clarify sex-based differences in outcomes for malignant-hematology patients with cachexia and sarcopenia, further research is needed.
Discussion
This review had international representation. Most of the research was from patients with NHL, the majority with DLBCL. Both PFS and OS are decreased when associated with cancer-related cachexia and sarcopenia. The question remains of the underlying cause of the decreased OS and PFS, the cancer, or the cachexia. If the disease is the primary cause, then treating the cancer aggressively should improve cancer-related cachexia and sarcopenia. This review shows that early identification of patients with hematologic malignancies and cancer-related cachexia and sarcopenia is necessary to provide increased support and improve health outcomes. Hematologic oncology patients with cachexia who are at increased risk are males with aggressive lymphoma, such as DLBCL. Transplant and CAR-T therapy are intensive treatments that also place patients at risk for the development of cancer-related cachexia and sarcopenia and deterioration in their physical function. These patients need increased multi-disciplinary support to tolerate treatment and minimize loss of function.
DLBCL is a potentially curable malignancy. Research in this review revealed that cancer-related cachexia and sarcopenia impact the toleration of the intended dose and cycles of chemo-immunotherapy, R-CHOP for DLBCL. Patients with DLBCL with a lower PNI had significantly more treatment-related mortality and treatment discontinuation among a higher percentage of patients, which resulted in lower response rates. Patients identified before treatment can benefit from enhanced support from dietitians, physical therapists, and the medical team for clinical practice. Patients who had LMD [ 31 ] terminated chemotherapy earlier because of treatment-related toxicity and early death. Hematologic parameters were correlated with cancer-related cachexia and sarcopenia, with anemia, thrombocytopenia, and febrile neutropenia occurring more frequently in cachectic and sarcopenic patients. This can be managed by more frequent monitoring of blood counts, close contact with the patient, and enhanced patient education.
Several studies in this review focused on identifying patients at risk for poor outcomes associated with cancer-related cachexia and sarcopenia. This review includes the cachexia score, Glasgow Prognostic Index, PNI, CXI, CIFs based on molecular signatures, GNRI, and a new CXI for patients with myeloproliferative neoplasms. The results are presented from studies using routine laboratory tests associated with nutrition and inflammation. There is no consensus on the best marker for identifying individuals at risk or for the definition of cancer-related cachexia. Using CRP at various thresholds is promising for assessing risk and diagnosing cancer-related cachexia and sarcopenia at earlier stages. In addition, albumin is an accepted measure of stored protein used to determine adequate nutritional status. It is a crucial laboratory parameter to include for evaluating sarcopenia and cancer-related cachexia. For dosing of chemotherapy, body mass index is calculated. This measure can be easily used to identify at-risk patients before beginning treatment.
Studies focused on radiologic determinations of patients at risk for and diagnosed with sarcopenia and cancer-related cachexia are in this review. This routine practice can be used in lymphoma patients to identify individuals who have cancer-related cachexia and sarcopenia who are at increased risk before beginning treatment. There is no consensus for the cutoff values or for an area of the body on a CT scan necessary to diagnose an individual with cancer-related cachexia or sarcopenia. Common radiologic areas of interest were the PMI, skeletal muscle mass and SMD, and L3 skeletal muscle. Although the definitions varied, these radiology studies reported worse outcomes for patients with lower PMI, lower skeletal muscle mass, especially muscle density, and lower overall skeletal muscle. This highlights the importance of a consensus for the cutoff values to further research to determine the optimal method for determining patients at the highest risk who may benefit from alterations in treatment or benefit from enhanced support during treatment with chemo-immunotherapy.
Only one study focused on the effect of treatment: autologous HSCT on cachexia [ 39 ]. Participants in this study had significant reductions in exercise capacity, lean mass, and fat mass. Cytokines did not explain the reduction in exercise capacity or lean and fat mass. The remaining studies concentrated on how cancer-related cachexia and sarcopenia predicted outcomes for transplanted patients and CAR-T–therapy patients. Consistent with studies using R-CHOP, having cachexia or sarcopenia was a risk factor for poor outcomes, including higher non-relapse mortality, longer hospitalizations, 100 days post-transplant re-admissions, increased odds of relapse at 90 days, and lower disease-free survival. This information is compelling for considering cancer-related cachexia and sarcopenia when discussing risks associated with transplants to patients who have cachexia and sarcopenia. The clinician must tailor the discussion to the patient’s unique needs outside the regular disease-related dialogue for transplant risk.
Another noteworthy finding in this review was the difference in the health outcomes between men and women with cancer-related cachexia and sarcopenia. In one study, OS and PFS were inferior for sarcopenia males only. In a separate prospective study, significant correlations between psoas indices and better Karnofsky performance status were observed only in men. Male sarcopenic patients had a significantly worse response to treatment. In contrast, another study of older patients found no statistically significant differences in OS or PFS between males and females diagnosed with DLBCL and treated with R-CHOP. Several studies showed worse outcomes for sarcopenic and cachectic males. However, conflicting results show the need for more research with larger numbers to increase our understanding of sex-based differences in health outcomes for patients diagnosed with a hematologic malignancy.
Strengths and limitations
The strengths of this integrative literature review included a thorough search of 4 databases by a biomedical librarian. In addition, 29 studies were conducted with representation from several countries. This allows the generalizability of the results to a broader, more ethnically diverse group. However, it is not without limitations. In this search and review, no randomized controlled trials are available due to the nature of the topic. It is not ethical to randomize participants to a cachectic or sarcopenic group. Retrospective studies limit the application of the results due to the nature of studies with inherent selection bias. Inconsistent use of terminology between cancer-related cachexia and cancer-related sarcopenia also limits conclusions while highlighting areas for further research. The absence of a definition of sarcopenia by CT imaging prevents comparison between studies. This limits the interpretation and comparison to real-world situations with varying disease states and CT-scan criteria for sarcopenia.
Clinical and research implications
Given the knowledge gaps discussed, more research is necessary to advance the science to prevent and treat cachexia in malignant hematologic diagnoses. One of the greatest needs is an improved awareness of cachexia and sarcopenia in patients with hematologic malignancies. In addition, research is needed to understand the pathophysiology of the process to tailor interventions and support patients and their caregivers. The following are future educational and research opportunities:
Differentiate terminology for consistent and accurate use in practice and research studies: cachexia, sarcopenia, and adipopenia.
Refine risk models for early identification of at-risk patients for cachexia further differentiated for sarcopenia and adipopenia.
Intervene early to minimize consequences for those patients at risk for cachexia and sarcopenia.
Examine the relationship of cachexia to incidence of toxicity, function, and overall survival.
Conclusions
Cancer-related cachexia and sarcopenia impact quality of life, OS, and PFS. The underlying pathophysiology of cachexia and sarcopenia is poorly understood, compounded by using terms interchangeably in research. Biomarkers are being studied, and several cachexia prognostic scores are in development. There is a near-nonexistent representation of myeloid neoplasms, with most research focusing on DLBCL. Ongoing prospective studies are needed to improve our recognition of the prevalence of cancer-related cachexia and sarcopenia and its contribution to poor outcomes. Increased awareness may enhance our support of patients and their caregivers to improve toleration of treatment and outcomes for overall and progression-free survival. Research focusing on improved understanding of pathophysiology will guide our methods to support the patients who are most affected.
Supplementary Material
Acknowledgments
Editorial assistance was provided by Moffitt Cancer Center’s Office of Scientific Publishing by Daley White and Gerard Hebert; no compensation was given beyond their regular salaries.
Mary Katherine Haver, MLIS, AHIP-D, Medical Librarian, Biomedical Library, Moffitt Cancer Center & Research Institute, for assistance with the literature search.
Funding
This work was supported by the National Institutes of Health [Grant 5K23NR018488 - National Institutes of Health – National Institute of Nursing Research], Gulf Coast Community Foundation
Declaration of competing interest
None.
CRediT authorship contribution statement
Sara M. Tinsley Vance: Data curation, Conceptualization, Formal analysis, Funding acquisition, Project administration, Visualization, Writing the original draft, Reviewing and editing. Tina Mason: Data acquisition, Formal analysis, Methodology, Project administration, Original draft writing, Review and editing. Rami Komrokji: Supervision, Reviewing and editing.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.hsr.2024.100205 .
References
[1] Roeland EJ , , Management of Cancer Cachexia: ASCO Guideline, (in eng) , J Clin Oncol 38 ( 21 ) ( 2020 ) 2438 – 2453 , 10.1200/JCO.20.00611 . 32432946
[2] Lim S , Brown JL , Washington TA , Greene NP , Development and progression of cancer cachexia: Perspectives from bench to bedside , Sports Med. Health Sci 2 ( 4 ) ( 2020 ) 177 – 185 , 10.1016/j.smhs.2020.10.003 . 34447946 PMC8386816
[3] von Haehling S , Anker SD , Prevalence, incidence and clinical impact of cachexia: facts and numbers-update 2014,” (in eng) , J. Cachexia Sarcopenia Muscle 5 ( 4 ) ( 2014 ) 261 – 263 , 10.1007/s13539-014-0164-8 . 25384990 PMC4248411
[4] Fearon K , , Definition and classification of cancer cachexia: an international consensus , The Lancet Oncol . 12 ( 5 ) ( 2011 ) 489 – 495 , 10.1016/S1470-2045(10)70218-7 . 21296615
[5] Porporato PE , Understanding cachexia as a cancer metabolism syndrome,” (in eng) , Oncogenesis . 5 ( 2 ) ( 2016 ), 10.1038/oncsis.2016.3e200 . PMC5154342 26900952
[6] Baracos VE , Martin L , Korc M , Guttridge DC , Fearon KCH , Cancer-associated cachexia , Nat. Rev. Disease Primers 4 ( 1 ) ( 2018 ) 17105 , 10.1038/nrdp.2017.105 . 29345251
[7] Arthur ST , Van Doren BA , Roy D , Noone JM , Zacherle E , Blanchette CM , Cachexia among US cancer patients,” (in eng) , J. Med. Econ 19 ( 9 ) ( 2016 ) 874 – 880 , 10.1080/13696998.2016.1181640 . 27100202
[8] Pressoir M , , Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres,” (in eng) , Br. J. Cancer 102 ( 6 ) ( 2010 ) 966 – 971 , 10.1038/sj.bjc.6605578 . 20160725 PMC2844030
[9] Hébuterne X , Lemaríe E , Michallet M , de Montreuil CB , Schneider SM , Goldwasser F , Prevalence of malnutrition and current use of nutrition support in patients with cancer,” (in eng) , JPEN. J. Parent. Enteral Nutr 38 ( 2 ) ( 2014 ) 196 – 204 , 10.1177/0148607113502674 . 24748626
[10] Li HL , , Different definition of sarcopenia and mortality in cancer: A meta-analysis,” (in eng) , Osteoporos. Sarcopenia 7 ( 2021 ) S34 – S38 , 10.1016/j.afos.2021.02.005 . Suppl 1. 33997307 PMC8088994
[11] Bauer J , , Sarcopenia: A Time for Action. An SCWD Position Paper,” (in eng) , J. Cachexia Sarcopenia Muscle 10 ( 5 ) ( 2019 ) 956 – 961 , 10.1002/jcsm.12483 . 31523937 PMC6818450
[12] Simmons LO , , AB020. 183. Prevalence of sarcopenia and its impact on survival in breast cancer—a systematic review and meta-analysis , Mesentery and Peritoneum 3 ( 1 ) ( 2019 ) [Online]Available , https://map.amegroups.com/article/view/4706 .
[13] Juez LD , , Impact of Sarcopenic Obesity on Long-Term Cancer Outcomes and Postoperative Complications After Gastrectomy for Gastric Cancer , J. Gastrointest. Surg 27 ( 1 ) ( 2023 ) 35 – 46 , 10.1007/s11605-022-05492-w,2023/01/01 . 36324039
[14] Roever L . ( 2018 ). PICO: Model for Clinical Questions .
[15] Moher D , Liberati A , Tetzlaff J , Altman DG , The PG , Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement , PLoS medicine 6 ( 7 ) ( 2009 ) e1000097 , 10.1371/journal.pmed.1000097 . 19621072 PMC2707599
[16] Critical Appraisal Skills Programme , CASP Checklists , CASP ( 2022 ). https://caspuk.net/casp-tools-checklists/ ( accessed 09/28 ,).
[17] Burkart M , , Evaluation of the impact of cachexia on clinical outcomes in aggressive lymphoma,” (in eng) , Br. J. Haematol 186 ( 1 ) ( 2019 ) 45 – 53 , 10.1111/bjh.15889 . 30941741
[18] Camus V , , Prognostic impact of fat tissue loss and cachexia assessed by computed tomography scan in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy,” (in eng) , Eur. J. Haematol 93 ( 1 ) ( 2014 ) 9 – 18 , 10.1111/ejh.12285 . 24520908
[19] Go SI , Park S , Kang MH , Kim HG , Kim HR , Lee GW , Clinical impact of prognostic nutritional index in diffuse large B cell lymphoma,” (in eng) , Ann. Hematol 98 ( 2 ) ( 2019 ) 401 – 411 , 10.1007/s00277-018-3540-1 . 30413902
[20] Poisson J , , Prevalence and prognostic impact of cachexia among older patients with cancer: a nationwide cross-sectional survey (NutriAgeCancer),” (in eng) , J. Cachexia Sarcopenia Muscle 12 ( 6 ) ( 2021 ) 1477 – 1488 , 10.1002/jcsm.12776 . 34519440 PMC8718093
[21] Lanic H , , Sarcopenia is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy,” (in eng) , Leukemia Lymphoma 55 ( 4 ) ( 2014 ) 817 – 823 , 10.3109/10428194.2013.816421 . 23781925
[22] Koyuncu MB , , Integration of low muscle mass into the IPS system and its prognostic significance in patients with Hodgkin’s lymphoma,” (in eng) , Biomark. Med 16 ( 2 ) ( 2022 ) 57 – 67 , 10.2217/bmm-2021-0696 . 34753299
[23] Lucijaníc M , , Psoas muscle index at the time of diagnosis might reflect the prognosis of classical Hodgkin’s lymphoma patients,” (in eng) , Wien. Klin. Wochenschr 134 ( 1–2 ) ( 2022 ) 80 – 82 , 10.1007/s00508-021-01850-x . 33835267
[24] Lucijanic M , Huzjan Korunic R , Sedinic M , Kusec R , Pejsa V , More Pronounced Muscle Loss During Immunochemotherapy is Associated with Worse Clinical Outcomes in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma with Unfavorable Features,” (in eng) , Ther. Clin. Risk. Manage 17 ( 2021 ) 1037 – 1044 , 10.2147/TCRM.S323749 . PMC8478493 34594106
[25] Karmali R , , Impact of cachexia on outcomes in aggressive lymphomas,” (in eng) , Ann. Hematol 96 ( 6 ) ( 2017 ) 951 – 956 , 10.1007/s00277-017-2958-1 . 28417157
[26] Go SI , , Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone,” (in eng) , J. Cachexia Sarcopenia Muscle 7 ( 5 ) ( 2016 ) 567 – 576 , 10.1002/jcsm.12115 . 27104110 PMC4833756
[27] Mallard J , , C-Reactive Protein Level: A Key Predictive Marker of Cachexia in Lymphoma and Myeloma Patients,” (in eng) , J. Hematol 8 ( 2 ) ( 2019 ) 55 – 59 , 10.14740/jh536 . 32300444 PMC7153683
[28] Nakamura N , , Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma,” (in eng) , Ann. Hematol 94 ( 12 ) ( 2015 ) 2043 – 2053 , 10.1007/s00277-015-2499-4 . 26385388
[29] Go SI , , Cachexia index as a potential biomarker for cancer cachexia and a prognostic indicator in diffuse large B-cell lymphoma,” (in eng) , J. Cachexia Sarcopenia Muscle 12 ( 6 ) ( 2021 ) 2211 – 2219 , 10.1002/jcsm.12837 . 34676685 PMC8718032
[30] Iltar U , , Prognostic impact of the psoas muscle index, a parameter of sarcopenia, in patients with diffuse large B-cell lymphoma treated with rituximab-based chemoimmunotherapy,” (in eng) , Leuk. Lymphoma 62 ( 5 ) ( 2021 ) 1098 – 1106 , 10.1080/10428194.2020.1856833 . 33300380
[31] Rier HN , , Prognostic impact of low muscle mass and low muscle density in patients with diffuse large B-cell lymphoma,” (in eng) , Leuk. Lymphoma 61 ( 7 ) ( 2020 ) 1618 – 1626 , 10.1080/10428194.2020.1737686 . 32167390
[32] Gnanaraj J , Parnes A , Francis CW , Go RS , Takemoto CM , Hashmi SK , Approach to pancytopenia: Diagnostic algorithm for clinical hematologists,” (in eng) , Blood Rev . 32 ( 5 ) ( 2018 ) 361 – 367 , 10.1016/j.blre.2018.03.001 . 29555368
[33] Fukushima T , , Characteristics of muscle function and the effect of cachexia in patients with haematological malignancy,” (in eng) , Eur. J. Cancer Care 28 ( 2 ) ( 2019 ), 10.1111/ecc.12956 e12956 . 30357948
[34] Kuang Z , Li X , Liu R , Chen S , Tu J , Comprehensive Characterization of Cachexia-Inducing Factors in Diffuse Large B-Cell Lymphoma Reveals a Molecular Subtype and a Prognosis-Related Signature , Front. Cell Dev. Biol 9 ( 2021 ) 648856 , 10.3389/fcell.2021.648856 . 34079795 PMC8166255
[35] Letilovic T , Perkov S , Mestric ZF , Vrhovac R , Differences in routine laboratory parameters related to cachexia between patients with hematological diseases and patients with solid tumors or heart failure - is there only one cachexia?,” (in eng) , Nutr. J 12 ( 6 ) ( 2013 ), 10.1186/1475-2891-12-6 . PMC3568018 23294910
[36] Tefferi A , , Development of a prognostically relevant cachexia index in primary myelofibrosis using serum albumin and cholesterol levels,” (in eng) , Blood Adv . 2 ( 15 ) ( 2018 ) 1980 – 1984 , 10.1182/bloodadvances.2018018051 . 30097464 PMC6093731
[37] Go SI , Kim HG , Kang MH , Park S , Lee GW , Prognostic model based on the geriatric nutritional risk index and sarcopenia in patients with diffuse large B-cell lymphoma , BMC. Cancer 20 ( 1 ) ( 2020 ) 439 , 10.1186/s12885-020-06921-2 . 32423395 PMC7236094
[38] Bas V , , Sarcopenia in Hodgkin’s lymphoma evaluated with 18-FDG PET/CT, focus on age, performance, and treatment , Support. Care Cancer 29 ( 5 ) ( 2021 ) 2475 – 2480 , 10.1007/s00520-020-05772-8 . 32929535
[39] Anderson LJ , , Assessing Cachexia Acutely after Autologous Stem Cell Transplant,” (in eng) , Cancers. (Basel) 11 ( 9 ) ( 2019 ), 10.3390/cancers11091300 . PMC6769803 31487803
[40] Caram MV , , Sarcopenia is associated with autologous transplant-related outcomes in patients with lymphoma,” (in eng) , Leuk. Lymphoma 56 ( 10 ) ( 2015 ) 2855 – 2862 , 10.3109/10428194.2015.1014359 . 25739940
[41] Williams A , , Prevalence and significance of sarcopenia in multiple myeloma patients undergoing autologous hematopoietic cell transplantation,” (in eng) , Bone Marrow Transp . 56 ( 1 ) ( 2021 ) 225 – 231 , 10.1038/s41409-020-01008-9 . PMC7855279 32732941
[42] Armenian SH , , Impact of Sarcopenia on Adverse Outcomes After Allogeneic Hematopoietic Cell Transplantation,” (in eng) , J. Natl. Cancer Inst 111 ( 8 ) ( 2019 ) 837 – 844 , 10.1093/jnci/djy231 . 30951603 PMC6695315
[43] Lin RJ , , The geriatric syndrome of sarcopenia impacts allogeneic hematopoietic cell transplantation outcomes in older lymphoma patients,” (in eng) , Leuk. Lymphoma 61 ( 8 ) ( 2020 ) 1833 – 1841 , 10.1080/10428194.2020.1742909 . 32228298 PMC7429343
[44] Nagayama T , , Impact of muscle mass loss assessed by computed tomography on the outcome of allogeneic stem cell transplantation,” (in eng) , Leuk. Lymphoma 63 ( 7 ) ( 2022 ) 1694 – 1700 , 10.1080/10428194.2022.2034159 . 35156892
[45] Roy I , , Cachexia is a risk factor for negative clinical and functional outcomes in patients receiving chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma,” (in eng) , Br. J. Haematol 197 ( 1 ) ( 2022 ) 71 – 75 , 10.1111/bjh.18054 . 35141891